Valve Prosthesis

ABSTRACT

The present disclosure relates to valve replacement devices that are foldable for catheter-based deployment to the site of implantation, as well as systems for the delivery of valve prostheses, including prostheses having the special characteristics of the disclosed valve replacement devices. The devices include highly effective adhering mechanisms for secure and enduring precision implantation. The adhering mechanisms may employ a unique sealing mechanism that includes a cuff that expands slowly whereby the device is not secured in place until the completion of the implantation procedure. The implanted device, optionally together with the cuff, prevents perivalvular leaks and incorporate an appropriate leaflet system for reliable functioning in situ.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation of U.S. Ser. No. 15/074,451, filedMar. 18, 2016, which is a continuation of U.S. Ser. No. 15/015,736,filed on Feb. 4, 2016, which is a continuation of U.S. Ser. No.13/505,885, filed on Aug. 7, 2012 (now U.S. Pat. No. 9,289,291, issuedon Mar. 22, 2016), which is the National Stage of InternationalApplication No. PCT/US2010/055645, filed Nov. 5, 2010, which claims thebenefit of U.S. Provisional Application No. 61/258,331 filed Nov. 5,2009, the entire disclosures of each of which are incorporated herein byreference.

TECHNICAL FIELD

The present disclosure relates to anatomical valve replacement devicesand methods and systems for replacing a valve and for delivering astented device.

BACKGROUND

The mitral valve is a complex structure whose competence relies on theprecise interaction of annulus, leaflets, chordae, papillary muscles andleft ventricle (LV). Pathologic changes in any of these structures canlead to valvular insufficiency. Myxomatous leaflet/chordal degeneration,and dilated ischemic cardiomyopathy secondary to chronic post infarctionventricular remodeling are among most common mechanisms producing mitralregurgitation (MR). These two disease processes account for about 78% ofall cases of MR treated surgically.

As part of the Framingham Heart Study, the prevalence of mitral valveprolapse in Framingham, Mass. was estimated at 2.4%. There was anear-even split between classic and non-classic MVP, with no significantage or sex discrimination. Based on data gathered in the United States,MVP is prevalent in 7% of autopsies. The incidence of mitralregurgitation increases with age and is a frequent clinicallysignificant medical problem in the post MI population and patients withCOPD.

The use of a catheter based percutaneous valved stent has been shown tobe feasible in replacing both the human pulmonic and aortic valves. Thepulmonic valve was the first to be successfully replaced by apercutaneous approach and is the furthest along in development. Thereare currently two aortic valve products in clinical trials and more indevelopment. While there is a great deal of interest in replacing themitral valve percutaneously (not least because many patients that havesuffered myocardial infarction are not fit for surgical valvereplacement) the anatomy and function of the mitral valve preventsdirect application of the current aortic/pulmonic technology. However,there have been recent efforts towards developing mitral valvereplacements that have focused on transapical valved stent implantation(see Lozonschi L, et al., Transapical mitral valved stent implantation.Ann Thorac Surg. 2008 September; 86(3): 745-8); “double-crown” valvedstent designs (see Ma L, et al., Double-crowned valved stents foroff-pump mitral valve replacement. Eur J Cardiothorac Surg. 2005 August;28(2):194-8); and, valved stent designs consisting of two disksseparated by a cylinder (see Boudjemline Y, et al., Steps toward thepercutaneous replacement of atrioventricular valves an experimentalstudy. J Am Coll Cardiol. 2005 Jul 19; 46(2): 360-5).

It has presently been discovered that a successful percutaneously placedvalve requires four major design characteristics. The valve must becompatible with acceptable delivery modalities, it must anchor to thevalvular ring and seal the anchor point to prevent leaks, and the valvemust function normally when in place. Among publicly available designs,there does not presently exist a percutaneous valved stent having thecharacteristics that are believed to be necessary for successfulimplantation, stability, and long-term functionality. A design havingsuch characteristics would have profound medical implications both forthose newly in need of valve replacement, and among patients that arecurrently fitted with conventional valve designs.

SUMMARY

In one aspect, valve prostheses are provided comprising a self-expandingstent comprising an outer surface, an interior surface, a middle region,an upper anchoring flange, and a lower anchoring flange, wherein thestent has an unexpanded and an expanded state; a cuff comprising anabsorbent material disposed at least partially circumferentially aroundthe outer surface of the stent, wherein the absorbent material expandsby absorption of a fluid to substantially adhere the prosthesis at animplantation site, and wherein the adhering is delayed for a timesufficient to permit positioning of the prosthesis at the implantationsite; and a valve comprising at least two leaflets fixedly attached tothe interior surface of the stent.

In another aspect, methods are disclosed for replacing a damaged ordiseased valve in a subject comprising: delivering to an implantationsite of the subject a mitral valve prosthesis comprising aself-expanding stent comprising an outer surface, an interior surface, amiddle region, an upper anchoring flange, and a lower anchoring flange,wherein the stent has an unexpanded and an expanded state; a cuffcomprising an absorbent material disposed at least partiallycircumferentially around the outer surface of the stent and a valvecomprising at least two leaflets fixedly attached to the interiorsurface of the stent; and expanding the cuff by absorption of a fluid tosubstantially adhere the prosthesis at an implantation site, wherein theadhering is delayed for a time sufficient to permit positioning of theprosthesis at the implantation site.

Also disclosed are valve prostheses comprising an at least partiallyself-expanding stent comprising a wire framework defining outer andinterior surfaces, and upper and lower anchoring flanges interposed by amiddle region, the stent having an unexpanded and an expanded state, andthe lower anchoring flange having at least one geometric dimension thatis greater than the corresponding dimension of the upper anchoringflange; and a valve comprising at least one leaflet fixedly attached tothe interior surface of the stent.

The present disclosure also includes methods for replacing a damaged ordiseased valve in a subject comprising: delivering to an implantationsite of the subject a valve prosthesis comprising an at least partiallyself-expanding stent comprising a wire framework defining outer andinterior surfaces, and upper and lower anchoring flanges interposed by amiddle region, the stent having an unexpanded and an expanded state, andthe lower anchoring flange having at least one geometric dimension thatis greater than the corresponding dimension of the upper anchoringflange; and a valve comprising at least one leaflet fixedly attached tothe interior surface of the stent; and expanding the stent tosubstantially adhere the prosthesis at the implantation site.

In another aspect, provided are systems for delivering a valveprosthesis comprising an at least partially self-expanding stent to animplantation site comprising: a catheter comprising a distal end and aproximal end, a guidewire lumen to permit the catheter to be translatedalong a guidewire, a steering lumen for accommodating a tension cablefor steering the catheter, and a dock at the distal end onto which thestent may be loaded. The present systems also comprise a retractablecompression sleeve for compressing at least a portion of the stent whilethe stent is loaded onto the dock; a leading tip positioned distal tothe dock for leading the catheter during delivery; and, a steeringmechanism operably associated with the tension cable for deflecting theleading tip in at least one directional plane.

In yet another aspect, there are disclosed kits comprising a systemcomprising an at least partially self-expanding stent to an implantationsite comprising: a catheter comprising a distal end and a proximal end,a guidewire lumen to permit the catheter to be translated along aguidewire, a steering lumen for accommodating a tension cable forsteering the catheter, and, a dock at the distal end onto which thestent may be loaded; a retractable compression sleeve for compressing atleast a portion of the stent while the stent is loaded onto the dock; aleading tip positioned distal to the dock for leading the catheterduring delivery; and, a steering mechanism operably associated with thetension cable for deflecting the leading tip in at least one directionalplane; and, at least one valve prosthesis comprising an at leastpartially self-expanding stent comprising a wire framework definingouter and interior surfaces, and upper and lower anchoring flangesinterposed by a middle region, the stent having an unexpanded and anexpanded state, and the lower anchoring flange having at least onegeometric dimension that is greater than the corresponding dimension ofthe upper anchoring flange; and a valve comprising at least one leafletfixedly attached to the interior surface of the stent.

The present disclosure also pertains to methods for delivering a valveprosthesis comprising an at least partially self-expanding stent to animplantation site comprising: (i) providing a system comprising acatheter comprising a distal end and a proximal end, a guidewire lumento permit the catheter to be translated along a guidewire, a steeringlumen for accommodating a tension cable for steering the catheter, and,a dock at the distal end onto which the stent may be loaded; aretractable compression sleeve for compressing at least a portion of thestent while the stent is loaded onto the dock; a leading tip positioneddistal to the dock for leading the catheter during delivery; and, asteering mechanism operably associated with the tension cable fordeflecting the leading tip in at least one directional plane; (ii)loading onto the dock the valve prosthesis; (iii) delivering a guidewireto the implantation site; (iv) translating the catheter over theguidewire so that the loaded valve prosthesis is positioned at theimplantation site; (v) retracting the retractable compression sleeve topermit the stent to expand at the implantation site and to undock fromthe catheter; and, (vi) removing the catheter and the guidewire from theimplantation site.

BRIEF DESCRIPTION OF THE DRAWINGS

The foregoing and other aspects of the present inventions will becomeapparent from the following detailed description when considered inconjunction with the accompanying drawings. For the purpose ofillustrating the invention, there is shown in the drawings embodimentsthat are presently preferred, it being understood, however, that theinvention is not limited to the specific aspects disclosed. The drawingsare not necessarily drawn to scale. In the drawings:

FIG. 1 shows three different views of an exemplary prosthesis accordingto the present disclosure.

FIG. 2 depicts a simplified version of an exemplary prosthesis featuringupper and lower flanges that comprise projections.

FIG. 3 illustrates steps from an exemplary procedure for transatrialdelivery of a prosthesis according to the present disclosure.

FIG. 4 depicts steps from an exemplary procedure for venous percutaneousdelivery of a prosthesis according to the present disclosure.

FIG. 5 provides views of an exemplary stent for use in a prosthesisaccording to the present invention.

FIG. 6 provides an illustrative example of how to characterize wireweave density, as well as how wire weave density and wire thicknessrespectively affect various parameters of the inventive stent.

FIG. 7 depicts the components of an exemplary kit according to thepresent disclosure.

FIGS. 8-9 illustrate an example of how retractable compression sleevesmay be used to compress a stent against the dock of a catheter duringdelivery to an implantation site, and to permit the stent to expand atthe implantation site and undock from the catheter.

FIG. 10 illustrates how the process described in FIG. 9 will result inthe implantation in situ of a valve prosthesis that comprises a wireframework.

DETAILED DESCRIPTION OF ILLUSTRATIVE EMBODIMENTS

The present inventions may be understood more readily by reference tothe following detailed description taken in connection with theaccompanying figures and examples, which form a part of this disclosure.It is to be understood that these inventions are not limited to thespecific products, methods, conditions or parameters described and/orshown herein, and that the terminology used herein is for the purpose ofdescribing particular embodiments by way of example only and is notintended to be limiting of the claimed inventions.

In the present disclosure the singular forms “a,” “an,” and “the”include the plural reference, and reference to a particular numericalvalue includes at least that particular value, unless the contextclearly indicates otherwise. Thus, for example, a reference to “amaterial” is a reference to one or more of such materials andequivalents thereof known to those skilled in the art, and so forth.When values are expressed as approximations, by use of the antecedent“about,” it will be understood that the particular value forms anotherembodiment. As used herein, “about X” (where X is a numerical value)preferably refers to ±10% of the recited value, inclusive. For example,the phrase “about 8” preferably refers to a value of 7.2 to 8.8,inclusive; as another example, the phrase “ about 8%” preferably (butnot always) refers to a value of 7.2% to 8.8%, inclusive. Where present,all ranges are inclusive and combinable. For example, when a range of “1to 5” is recited, the recited range should be construed as includingranges “1 to 4”, “1 to 3”, “1-2”, “1-2 & 4-5”, “1-3 & 5”, “2-5”, and thelike. In addition, when a list of alternatives is positively provided,such listing can be interpreted to mean that any of the alternatives maybe excluded, e.g., by a negative limitation in the claims. For example,when a range of “1 to 5” is recited, the recited range may be construedas including situations whereby any of 1, 2, 3, 4, or 5 are negativelyexcluded; thus, a recitation of “1 to 5” may be construed as “1 and 3-5,but not 2”, or simply “wherein 2 is not included.”

Unless otherwise specified, any component, element, attribute, or stepthat is disclosed with respect to one aspect of the present invention(for example, the prostheses, systems, kits, and methods, respectively)may apply to any other aspect of the present invention (any other of therostheses, systems, kits, and methods, respectively) that is disclosedherein

The disclosures of each patent, patent application, and publicationcited or described in this document are hereby incorporated herein byreference, in their entirety.

It has previously been demonstrated that the use of catheter-basedpercutaneous valved stents is feasible for the replacement of both ofhuman pulmonic and human aortic valves. Replacement of the pulmonicvalve was the first to be successfully performed using a percutaneousapproach, and is presently the furthest along in development. Whilethere is a great deal of interest in replacing the mitral valvepercutaneously, the anatomy and function of the mitral valve preventsdirect application of the technology that is currently applicable topulmonic and aortic valve replacement. There are presently a significantnumber of patients that suffer from mitral valve incompetence due toleft ventricular dysfunction after a myocardial infarction. However,many of these patients are deemed too fragile to undergo surgical mitralvalve replacement or repair. The development of a catheter-basedtechnology for reliable replacement of the mitral valve would allow suchpatients to be included among those subjects who are eligible forlife-saving mitral valve replacement therapy. It has presently beendiscovered that successful percutaneously delivered valve should possessfour main design characteristics: it must be foldable or collapsible fordelivery; it must anchor to the valvular ring; it must seal theimplantation point to prevent leaks; and, the valve itself must functionnormally when in situ. The presently disclosed valve replacements arefoldable for catheter-based deployment to the site of implantation,include highly effective anchoring mechanisms for secure and enduringprecision implantation, employ unique sealing mechanisms that preventsperivalvular leaks, and incorporates an appropriate leaflet system forreliable functioning in situ.

General Embodiment I

The following disclosure pertains to a first general embodiment of thepresent disclosure, which pertains to inventive valve prostheses andmethods for replacing a damaged or diseased valve.

In one aspect, valve prostheses are provided comprising a self-expandingstent comprising an outer surface, an interior surface, a middle region,an upper anchoring flange, and a lower anchoring flange, wherein thestent has an unexpanded and an expanded state; a cuff comprising anabsorbent material disposed at least partially circumferentially aroundthe outer surface of the stent, wherein the absorbent material expandsby absorption of a fluid to substantially adhere the prosthesis at animplantation site, and wherein the anchoring is delayed for a timesufficient to permit positioning of the prosthesis at the implantationsite; and a valve comprising at least two leaflets fixedly attached tothe interior surface of the stent. In preferred embodiments, theprosthesis is a mitral valve prosthesis.

The stent may be self-expanding, or may be configured to be forciblyexpanded, for example, by a balloon. In preferred embodiments, the stentis self-expanding. The self-expanding stent preferably comprises ashape-memory or “superelastic” material exhibiting large elasticstrains. An exemplary material is nitinol, a nickel-titanium alloy. Anyother material possessing similar characteristics may also be used inthe construction of the self-expanding stent, and more generally, andsuitable, biocompatible material may be used to form the stent, whetherit is self-expanding or not. Exemplary materials include stainlesssteel, cobalt/chromium alloy, cobalt/chromium/nickel alloy,nickel/chromium alloy, platinum, platinum/iridium alloy, among others.The stent may comprise one or more other materials that are themselvesnot self-expanding but that do not inhibit or otherwise interfere withthe ability of the stent to self-expand. For example, any biocompatiblematerial may be included to add any other desired structural feature tothe stent. Exemplary biocompatible materials include stainless steel,tantalum, platinum alloys, niobium alloys, and cobalt alloys, amongothers. Additionally or alternatively, one or more bioabsorbablematerials may be used in forming the stent. Part or all of the stent maybe coated with a composition comprising a drug, so that the stent iscapable of eluting drug in situ. The stent preferably comprises aframework that is formed from the material that allows the stent to beself-expanding, in addition to any other compatible materials asdescribed above. The structural framework can be formed from wire usingconventional techniques, such as coiling, weaving, braiding, orknitting. The wire may be welded or otherwise joined at some or allcrossover points, thereby forming a structure that is not hinged. Theformation of stents is readily appreciated among those skilled in theart and the present disclosure is intended to embrace any suitabletechnique, including any functionally acceptable stent geometry.

The stent comprises a middle region having various dimensions, includingan unexpanded length, an unexpanded outer circumference, an expandedlength, and an expanded outer circumference. The unexpanded length ispreferably substantially the same as or greater than the expandedlength, and the expanded outer circumference is greater than theunexpanded outer circumference. The unexpanded outer circumference maybe any size that enables the unexpanded stent to be translated throughthe interior of a catheter. For example, the unexpanded outercircumference may be of a size that enables the unexpanded stent to betranslated along the interior of a catheter having a diameter of about 1mm to about 8 mm. The expanded length preferably substantiallycorresponds to the length that is about the same as or longer than thatof the annulus between the left atrium and left ventricle of a humansubject's heart. Preferably, the expanded length of the stent is longerthan that of the annulus between the left atrium and left ventricle.Because the length of the mitral valve annulus may vary from subject tosubject, a particular subject may be matched with a stent having anexpanded length that is appropriate for the mitral valve annulus of thatsubject. In general, the expanded length may be about 0.5 cm to about 5cm, about 1 cm to about 4 cm, about 1.5 cm to about 3.5 cm, or about 2cm to about 3 cm. The expanded outer circumference may be substantiallythe same as or less than the inner circumference of a subject's mitralvalve annulus. In preferred embodiments, the expanded outercircumference is less than the inner circumference of a subject's mitralvalve annulus, and is appropriately sized such that the stent having acuff that is disposed at least partially circumferentially around theouter surface of the stent can be positioned within the mitral valveannulus. As discussed more fully herein, the cuff has an unexpanded formand an expanded form, and the stent is preferably appropriately sizedsuch that the stent having a substantially unexpanded cuff disposed atleast partially circumferentially around the outer surface of the stentcan be positioned within the mitral valve. In general, the expandedouter circumference of the stent may be about 2 cm to about 5 cm, about2.5 cm to about 4 cm, or about 2.5 cm to about 3.5 cm.

The prostheses according to the present disclosure may be configured tobe delivered transatrially, transapically, or percutaneously. Thus, thedimensions of the prosthesis, the type of material used for the stent,cuff, or other components, the presence or absence of a drug coating onthe stent, the type of flanges that are included, the weave pattern ofthe stent, the length of delay of absorption of fluid, and other factorsmay all be manipulated in order to configure the prosthesis fortransatrial, transapical, or percutaneous delivery, as desired. Thoseskilled in the art will readily appreciate the characteristics that arerequired for delivery of a stented device by the transatrial,transapical, or percutaneous route, respectively, and may selectaccordingly from the wide range of characteristics described herein.

In addition to the middle region the self-expanding stent comprises anupper and a lower flange. In the most simple embodiment, one or both ofthe flanges comprise the longitudinal ends or margins of the middleregion. For example, one or both of the flanges may be a “lip” ofmaterial that extends partly or fully around the circumference of thestent at a longitudinal end of the middle region. In other embodiments,one or both of the flanges may be configured to provide an anchoringfunctionality that substantially affixes the stent at the location ofthe mitral annulus. In particular, one of the upper or lower flanges maybe configured to anchor to the ventricular side of the mitral annulus,and the other of the upper or lower flanges may be configured to anchorthe atrial side of the mitral annulus. The upper flange, lower flange,or both may comprise a plurality of protruding stent elements. Forexample, if the stent is constructed from wire, the flanges may comprisea plurality of individual wires or bundled sets of wires. The pluralityof wires may comprise a regularly or irregularly spaced array, and thewires themselves may be present as single strands, or as grouped orbundled sets of two, three, four, or more wire strands. Each flange mayhave a configuration that corresponds to the unexpanded state of thestent, and a configuration that corresponds to the expanded state of thestent. When one or both of the flanges comprise a plurality ofindividual stent elements, the elements may be substantiallystraightened when the stent is in the unexpanded state and may besubstantially coiled when the stent is in the unexpanded state. In otherembodiments, a flange may comprise one or more elements that defineflaps, lobes, or other projections that may be oriented substantiallyparallel with the long axis of the stent when the stent is in anunexpanded state and oriented at a substantially oblique angle (forexample, about 30°, about 45°, about 60°, about 75°, or about 90°)relative to the long axis of the stent when the stent is in an expandedstate. FIG. 2 provides a simplified view of an exemplary embodiment ofthis variety, having flaps 7 that are oriented substantially parallelwith the long axis Y when stent 4 is in an unexpanded state (FIG. 2A)and that are oriented at a substantially oblique angle relative to the“long” axis Y when stent 4 is an expanded state. Any flange design,whether consisting of a unitary structure or numerous discrete elements,is contemplated for purposes of the present disclosure.

The present mitral valve prostheses also comprise a cuff comprising anabsorbent material that is disposed at least partially circumferentiallyaround the outer surface of the stent. The term “cuff” is intended toembrace a continuous ring of absorbent material that forms a completecircle around the outer surface of the stent; any other conformationthat involves a contiguous portion of absorbent material, such as astrip that forms a spiral around the outer surface of the stent; one,two, three or more disparate patches or strips (or any other shape orconfiguration) of absorbent material disposed on the outer surface ofthe stent; or, any combination of one or more contiguous portions ofmaterial and disparate patches, strips, and the like. In a preferredembodiment, the cuff comprises a continuous ring of absorbent materialthat forms a complete circle around the outer surface of the stent.

The cuff comprises an absorbent material that expands by absorption of afluid to substantially adhere the prosthesis at the implantation site.When the disclosed prostheses are used to replace a damaged ornonfunctional mitral valve, the implantation site is the mitral valveannulus. As used herein to “adhere” may mean to substantially affix oranchor the prosthesis at the implantation site, to create a seal betweenthe cuff and the mitral valve annulus that is substantially impermeableto fluid, or both. It has been presently discovered that the cuff canform a seal that reliably prevents perivalvular leakage between theatrium and ventricle, such that when the prosthesis is in place, theonly fluid that passes between the atrium and ventricle is that which isallowed to pass by the activity of the replacement valve itself

The adhering of the prosthesis is delayed for a time sufficient topermit positioning of the prosthesis at the implantation site. Forexample, because the procedure for positioning the prosthesis via acatheter at the implantation site may last 40 minutes, the expansion bythe cuff by absorption of fluid to a sufficient degree such as to adherethe prosthesis to the implantation may be delayed until that time haselapsed. Thus, the cuff comprises one or more materials, components, orboth that creates a delay in the absorption of fluid or that provides asufficiently slow rate of absorption of the fluid, such that the cuffdoes not expand to the degree required to adhere the prosthesis to theimplantation site until the desired period of delay has elapsed. Theperiod of delay may be measured starting at the point in time where theprosthesis is exposed to a fluid (e.g., blood). The delay period may beabout 1 minute, about 2 minutes, about 5 minutes, about 7 minutes, about10 minutes, about 15 minutes, about 20 minutes, about 30 minutes, about45 minutes, about 1 hour, about 75 minutes, about 90 minutes, or about 2hours. The type of cuff that is selected for use with the prosthesis maydepend on the difficulty of the procedure to deliver the prosthesis tothe implantation site.

The absorbent material of the cuff may itself absorb fluid at asufficiently slow rate to delay the adhering of the prosthesis at theimplantation site. In other embodiments, the absorbent material of thecuff may feature a variable rate of absorption, such that the rate ofabsorption is low for an initial period of time but that increases overtime or after a period of time. For example, the absorbent material mayhave a fluid absorption rate of about 0 μL to about 20 μL per minute fora first period of time following exposure of the prosthesis to thefluid, and a fluid absorption rate from about 10 to about 200 μL perminute after the first period of time. The period of time after whichthe rate of absorption increases may be about 10 minutes, about 15minutes, about 20 minutes, about 30 minutes, about 45 minutes, about 1hour, about 90 minutes, about 2 hours, about 180 minutes, or about 2hours. In other embodiments, the ability of the absorbent material ofthe cuff to absorb fluid is delayed. For example, the absorbent materialof the cuff may be completely or partially covered with or containedwithin a material that affects the ability of the absorbent material toabsorb fluid. The absorbent material may be completely or partiallycovered with or contained within a cover material, e.g., a film orfabric, that is permanently impermeable to fluid, but that is removableand is removed when the desired period of delay has elapsed; the removalof the cover material may be effected while the prosthesis is in situ atthe implantation site, for example, by using a catheter-based removaltool to grasp and remove the cover material. Any material that issubstantially impermeable to fluid (such as water, blood, and the like)and that is biocompatible may be used to form the cover material.Nonlimiting examples include polyurethanes, polyethylenes,polydimethylsiloxane, silicones, rubbers, and polyvinyl chloride. Inother embodiments, the absorbent material may be completely or partiallycovered with or contained within a cover material, e.g., a film orfabric, that is temporarily impermeable to fluid, but that becomespermeable to fluid after a desired period of delay. For example, thecover material may be degradable over time, or may comprise a materialthat degrades or is altered in response to a change in temperature, pH,or some other environmental cue that is present at the implantationsite. In other embodiments, the absorbent material may be completely orpartially covered with or contained within a cover material that ispermeable to fluid, but the transfer of fluid across such cover materialand/or saturation of by the cover material by fluid is sufficiently slowto provide a delay before the absorbent material absorbs a sufficientamount of fluid to adhere to the implantation site. The period of delaythat is provided by a cover material may be, for example, about 5minutes to about 3 hours, about 10 minutes to about 3 hours, about 20minutes to about 2 hours, about 30 minutes to about 2 hours, about 45minute to about 90 minutes, or about one hour following exposure of theprosthesis to a fluid. In still other embodiments, the ability of theabsorbent material of the cuff to absorb is delayed because theabsorbent material itself or a material that is mixed in or otherwisesubstantially interspersed or integrated with the absorbent material isaltered in response to one or more conditions (e.g., temperature, pH,and the like) that are present at the implantation site. For example,the absorbent material may include or may be provided along with apolymer that changes shape over time in response to exposure to thefluid or some other environmental cue present at the implantation site,and such shape change permits the initiation or the acceleration of theabsorption of fluid by the absorbent material.

Exemplary substances that may be used to form the absorbent materialinclude any crosslinked hydrogel component. A crosslinked hydrogelcomponent may be based on covalent crosslinks, physical/ioniccrosslinking, or both. Nonlimiting examples include poly(acrylic acid),poly(ethylene glycol), poly(ethylene oxide), poly(propylene oxide),poly(vinyl alcohol), polyvinyl pyrrolidinone, poly(hydroxy ethylmethacrylate), poly(amino acids), Dextran, polysaccharides, andproteins. Further examples of substances that may be used to form theabsorbent material include sodium polyacrylate, polyacrylamidecopolymer, ethylene maleic anhydride copolymer, carboxy-methyl-cellulosepolyvinyl alcohol copolymers, polyethylene oxide, and polyacrylonitrile.

Any “super absorbent” material, for example, a super absorbent polymer,also may be used. As used herein, a “super absorbent” material is onethat features an increase in volume swelling ratio (Qv; swollen volumedivided by “dry” volume or volume before any fluid has been absorbed)from 1 to about 5-1000. Some examples of super absorbent materials arelisted above. Those of ordinary skill in the art can readily identifyother suitable materials that may be characterized as “super absorbent”and any such material may be used. Preferably, the cuff is configured sothat expansion occurs predominantly in a single direction. For example,the expansion may predominantly in a direction that is substantiallyperpendicular relative to the outer surface of the stent. If the cuffcomprises a continuous ring of absorbent material that forms a completecircle around the outer surface of the stent, the direction of expansionof the absorbent material may be characterized as radial. Because thestent in its expanded state will be sufficiently rigid to resistcompression as a result of any radial expansion by the absorbentmaterial in the direction towards the surface of the stent, the radialexpansion of the absorbent material will be substantially unidirectionalin the direction away from the surface of the stent, i.e., towards theinterior surface of the mitral valve annulus. As described above, theexpansion of the absorbent material creates a seal between the cuff andthe mitral valve annulus that prevents perivalvular leakage.

A prosthesis according to the present disclosure may further comprise awebbing that is disposed at the upper flange, lower flange, or both. Thewebbing may comprise an absorbent material. The presence of the webbingmay assist with the adhering (i.e., the affixing, anchoring, and/orsealing) of the prosthesis at the implantation site. Accordingly, thewebbing may expand by absorption of a fluid, and the resulting adheringmay be delayed for a time sufficient to permit positioning of theprosthesis at the implantation site. When one or both of the upper andlower flanges comprise discrete elements, such as individual stentelements as described above, a portion of the webbing may be disposedbetween at least one pair of the individual stent elements of either orboth of the flanges. Preferably, the webbing is disposed between aplurality of pairs of individual stent elements of the upper anchoringflange and between a plurality of pairs of individual stent elements ofthe lower anchoring flange. When one or both of the upper and lowerflanges comprise flaps, lobes, or other projections, part or all of eachof the projections may be fitted with webbing. Each of thecharacteristics of the materials or components that are described abovewith respect to the cuff may be present in the webbing. Thus, thewebbing the may comprise one or more materials, components, or both thatcreates a delay in the absorption of fluid or that provides asufficiently slow rate of absorption of the fluid, such that the webbingdoes not expand to the degree required to adhere the prosthesis to theimplantation site until the desired period of delay has elapsed.

The prostheses of the invention also comprise a valve comprising atleast one leaflet that is fixedly attached to the interior surface ofthe stent. The attachment of the leaflet or leaflets to the interiorsurface of the stent need not be direct; for example, a valve supportring may be fixedly attached to the interior surface of the stent, andthe valve(s) may be fixedly attached to the valve support ring. Thevalve may comprise one leaflet, two leaflet, or three leaflets. Theleaflets are preferably derived from a biological source, such asmammalian pericardium. For example, the leaflets may be made frombovine, equine, ovine, caprine, or porcine pericardium. In otherembodiments, the leaflets may be derived from animal valves, preferablymammalian valves. Nonlimiting examples include bovine jugular veinvalves, porcine pulmonary valves, and porcine aortic valves. Those ofordinary skill in the art will appreciate how to select the appropriatevalve for the desired purpose.

FIG. 1 provides three views of an exemplary prosthesis 2. Prosthesis 2comprises a stent 4 having an upper anchoring flange 6 and a loweranchoring flange 8. As shown in FIGS. 1A and 1C, respectively, stent 4has an expanded state and an unexpanded state. FIG. 1B provides a topperspective of exemplary prosthesis 2. Upper flange 6 and lower flange 8comprise individual stent elements that are substantially coiled whenstent 4 is in the expanded state (FIGS. 1A, 1B) and are substantiallystraightened when stent 4 is in the unexpanded state (FIG. 1C). As stent4 is compressed and elongated, the stent elements also elongate andstraighten to allow prosthesis 2 to fold and fit through a positioningcatheter. Prosthesis 2 also comprises a cuff 10 a, 10 b that is disposedcircumferentially around the outer surface of stent 4. As shown in FIG.1C, before prosthesis 2 is positioned at the site of implantation, cuff10 a will not have expanded by absorption of fluid. However, as depictedin FIGS. 1A and 1B, once prosthesis 2 has been exposed to fluid and thedesired amount of time has elapsed for positioning prosthesis 2 at theimplantation site, cuff 10 b will have absorbed fluid and expandedradially in the direction substantially away from the surface of stent 4to substantially adhere prosthesis 2 at the implantation site.Prosthesis 2 also includes leaflets 12 that are fixedly attached to theinterior surface of stent 4. The prosthesis depicted in FIG. 1 includesthree leaflets, which can most clearly be ascertained in FIG. 1B.

In another aspect, there are disclosed methods for replacing a damagedor diseased mitral valve in a subject comprising: delivering to animplantation site of the subject a mitral valve prosthesis comprising aself-expanding stent comprising an outer surface, an interior surface, amiddle region, an upper anchoring flange, and a lower anchoring flange,wherein the stent has an unexpanded and an expanded state; a cuffcomprising an absorbent material disposed at least partiallycircumferentially around the outer surface of the stent and a valvecomprising at least two leaflets fixedly attached to the interiorsurface of the stent; and expanding the cuff by absorption of a fluid tosubstantially adhere the prosthesis at an implantation site, wherein theadhering is delayed for a time sufficient to permit positioning of theprosthesis at the implantation site.

Each of the attributes, components, materials, and the like that aredescribed above with respect to the inventive mitral valve prosthesesmay be used in accordance with the present methods.

Delivery of the mitral valve prosthesis to an implantation site may beaccomplished transatrially, transapically, or percutaneously. Deliveryof the prosthesis may be followed by one or more positioning steps(i.e., positioning and, if desired, repositioning), whereby the locationof the prosthesis may be adjusted for optimal positioning in relation tothe mitral valve annulus.

For transatrial delivery, an exemplary procedure may be performed asfollows and as illustrated in FIG. 3. A small (2-3 cm) thoracotomythrough the inter costal space is made (FIG. 3A). The inter-atrial planeis developed. As shown in FIG. 3B, the right atrium 14 is retracted, anda purse string suture is placed in the left atrium 16. Right pulmonaryveins are shown as item 18. Then, a steerable introducer catheter 20 isplaced into the left atrium through the purse string (FIG. 3C). Thecatheter is advanced through the mitral valve annulus (FIG. 3D). Itsposition may be guided and confirmed by echocardiography. The prosthesis2 is introduced through the catheter 20. The ventricular flange expandsfirst and anchors to the ventricular side of the annulus and thesubvalvular apparatus (leaflets, chordea, left ventricular wall) (FIG.3E). The remainder of the stent and atrial flange are delivered, alsounder echocardiographic guidance (not shown). The atrial flange expandsand anchors to the annulus and left atrium. The sealing cuff remainsflaccid during the ensuing 60 minutes to allow documentation byechocardiography that the valve's position and function are adequate.After an hour in place the cuff 10 b fully expands to seal the deviceagainst the native mitral valve annulus (FIG. 3F).

For transapical delivery, an exemplary procedure may be performed asfollows. A small left thoracotomy is performed—similar in size to thatwhich is used during the transatrial delivery procedure. A purse stringsuture is place in the left ventricular apex. A steerable catheterintroducer is then placed into the left ventricle through the pursestring. The introducer catheter 20 is guided through the mitral valveannulus into the left atrium under echocardiographic guidance. For thisapproach, the device may be designed so that the atrial flange isdeployed and positioned first. The sealing technology by means of thecuff and optional webbing may be similar to that described above withrespect to the exemplary transatrial delivery process.

Percutaneous delivery may be venous or arterial. When percutaneousdelivery is the intended procedure, the prosthesis is configuredaccordingly, e.g., foldable enough to be placed via peripheral venous orarterial access.

Venous percutaneous delivery may be performed as follows and asillustrated in FIG. 4. Access to the femoral vein is achieved bystandard techniques that will be readily appreciated by those skilled inthe art. A steerable catheter 20 is then introduced into the venoussystem and guided to the right atrium using fluoroscopic guidance (FIG.4A). Once in the right atrium, standard techniques are used to traversethe catheter across the intra-atrial septum to the left atrium (FIG.4B). The prosthesis 2 is then deployed under echocardiographic guidanceas described in the transatrial approach.

For aterial percutaneous delivery, an exemplary procedure may beperformed as follows. Access to the femoral artery is achieved bystandard techniques. A steerable catheter is then introduced into thearterial system and guided to the aortic root and into the leftventricle using fluoroscopic guidance. Once in the left ventricle thedevice is deployed as described above in connection the transapicalapproach.

General Embodiment II

The following description pertains to a second general embodiment of thepresent disclosure, which pertains to inventive valve prostheses;methods for replacing a damaged or diseased valve; systems fordelivering a valve prosthesis; kits; and, methods for delivering a valveprosthesis.

In one aspect, provided are valve prostheses comprising an at leastpartially self-expanding stent comprising a wire framework definingouter and interior surfaces, and upper and lower anchoring flangesinterposed by a middle region, the stent having an unexpanded and anexpanded state, and the lower anchoring flange having at least onegeometric dimension that is greater than the corresponding dimension ofthe upper anchoring flange; and a valve comprising at least one leafletfixedly attached to the interior surface of the stent.

The stent may be configured to be at least partially self-expanding. Forexample, the stent may be capable of self-expanding to its state ofmaximal expansion, or, to at least some degree, the stent may beconfigured such that it must be forcibly expanded, for example, by aballoon. For example, the stent may be configured so that 100% of itsrequisite expansion occurs without any contribution by a mechanism otherthan the stent itself, or may be configured so that 99% or less, butmore than 0%, of the requisite expansion occurs without any contributionby a mechanism other than the stent itself. In certain embodiments, thestent is fully self-expanding.

The at least partially self-expanding stent may comprise a shape-memoryor “superelastic” material exhibiting large elastic strains. Anexemplary material is nitinol, a nickel-titanium alloy. In oneembodiment, the stent comprises a nitinol wire weave. Any other materialpossessing similar characteristics may also be used in the constructionof the self-expanding stent, and more generally, and suitable,biocompatible material may be used to form the stent, whether it isself-expanding or not. Exemplary materials include stainless steel,cobalt/chromium alloy, cobalt/chromium/nickel alloy, nickel/chromiumalloy, platinum, platinum/iridium alloy, among others. The stent maycomprise one or more other materials that are themselves notself-expanding but that do not inhibit or otherwise interfere with theability of the stent to self-expand. For example, any biocompatiblematerial may be included to add any other desired structural feature tothe stent. Exemplary biocompatible materials include stainless steel,tantalum, platinum alloys, niobium alloys, and cobalt alloys, amongothers. Additionally or alternatively, one or more bioabsorbablematerials may be used in forming the stent. Part or all of the stent maybe coated with a composition comprising a drug, so that the stent iscapable of eluting drug in situ.

The stent comprises a wire framework that is formed from the materialthat allows the stent to be at least partially self-expanding, inaddition to any other compatible materials as described above. Theframework can be formed from wire using conventional techniques, such ascoiling, weaving, braiding, or knitting. In a preferred embodiment, thestent comprises a wire weave. In certain embodiments, the wire frameworkmay be welded or otherwise joined at some or all crossover points,thereby forming a structure that, at least in some places, is nothinged. The formation of wire frameworks is readily appreciated amongthose skilled in the art and the present disclosure is intended toembrace any suitable technique, including any functionally acceptableframework geometry.

The present inventors have found that the amount of radial force that isexerted by a stent can be an important determinant both of how well thestent will be anchored to the site of implantation and of the quality ofthe seal that is formed between the stent and the site of implantation,e.g., between the stent and the inner walls of a valve annulus. Pursuantto the present invention, it has been discovered that at least threefactors contribute to the outward radial force that the stent exerts.First, the thickness of the wire that is used to form the frameworkinfluences the degree of radial force that the stent exerts. Inaccordance with the present disclosure, the thickness of the wire thatis used to form the framework may be about 0.005 inches to about 0.030inches. For example, the wire may have a thickness of about 0.010inches, about 0.015 inches, about 0.020 inches, about 0.025 inches, orabout 0.030 inches. It has also been discovered that the density of thewire framework affects the radial force that is exerted by the stent.The parameters that can be used to describe the density of the wireframework are defined more fully infra. Third, the radial force that isexerted by the stent is influenced by the diameter of the stent in theexpanded state relative to the diameter of the major dimension of thevalve annulus into which the stent is to be implanted. Valve annuli maybe roughly circular, but in many instances are substantially ellipticalor saddle-shaped, such that the annulus will have a major and a minordimension (diameter). In the case of a circular annulus, the “majordimension” will simply be the diameter of the annulus. It has presentlybeen discovered that the stent exerts a beneficial amount of radialforce when the diameter of the stent in its expanded state is about 95%to about 125% of the major dimension of the valve annulus. For example,an expanded stent having a diameter that is about 95%, about 100%, about105%, about 110%, about 115%, about 120%, or about 125% of the majordimension of the valve annulus will be conducive to the exertion of abeneficial amount of radial force. Stated, in absolute terms, this canmean that an expanded stent may have a diameter of about 25 to about 50mm.

The stent comprises a middle region having various dimensions, includingan unexpanded length, an unexpanded diameter, an expanded length, and anexpanded diameter. The unexpanded length is preferably substantially thesame as or greater than the expanded length, and the expanded diameteris greater than the unexpanded diameter. The unexpanded diameter may beany size that enables the unexpanded stent to be translated through asubject's vasculature during delivery. For example, the unexpandeddiameter may be of a size that enables the unexpanded stent to fitwithin the interior of a catheter (or a related component, such as acompression sleeve, which is more fully described herein) having adiameter of about 1 mm to about 13 mm, preferably about 1 mm to about 8mm. The expanded length may substantially correspond to the length thatis about the same as or longer than that of the annulus between twochambers of a human subject's heart, or between one chamber and theassociated artery, such as the left ventricle and the aortic artery.Preferably, the expanded length of the stent is longer than that of suchan annulus. Because the length of a valve annulus, such as the mitralvalve annulus, may vary from subject to subject, a particular subjectmay be matched with a stent having an expanded length that isappropriate for the valve annulus of that subject. In general, theexpanded length may be about 0.5 cm to about 5 cm, about 1 cm to about 4cm, about 1.5 cm to about 3.5 cm, or about 2 cm to about 3 cm. Asdescribed above, the expanded diameter may be about 95% to about 125% ofthe major dimension of the subject's valve annulus. Even in embodimentswherein the present prosthesis further comprises a cuff comprising anabsorbent material that is disposed at least partially circumferentiallyaround the outer surface of the stent, which is discussed more fullyherein, the expanded diameter preferably falls within the range recitedabove relative to the major dimension of the subject's valve annulus.

The prostheses according to the present disclosure may be configured tobe delivered transatrially, transapically, or percutaneously. Thus, thedimensions of the prosthesis, the type of material used for the stent,cuff, or other components, the presence or absence of a drug coating onthe stent, the type of flanges that are included, the framework pattern(e.g., weave) of the stent, the length of delay of absorption of fluid,and other factors may all be manipulated in order to configure theprosthesis for transatrial, transapical, or percutaneous delivery, asdesired. Those skilled in the art will readily appreciate thecharacteristics that are required for delivery of a stented device bythe transatrial, transapical, or percutaneous route, respectively, andmay select accordingly from the wide range of characteristics describedherein.

In addition to the middle region the self-expanding stent comprises anupper flange and a lower flange. In the most simple embodiment, one orboth of the flanges comprise the longitudinal ends or margins of themiddle region. For example, one or both of the flanges may be a “lip” ofstent material that extends partly or fully around the circumference ofthe stent at a longitudinal end of the middle region. In otherembodiments, one or both of the flanges may be configured to provide ananchoring functionality that substantially affixes the stent at thelocation of the valve annulus. For example, the lower flange may beconfigured to anchor to the ventricular side of a mitral annulus, andthe upper flange may be configured to anchor to the atrial side of themitral annulus. The respective configurations of the upper and lowerflange may, but need not be, the same; thus, the lower flange may adopta different configuration than the upper flange. The upper flange, lowerflange, or both may comprise a plurality of protruding stent elements.Any flange design, whether consisting of a unitary structure or numerousdiscrete elements, is contemplated for purposes of the presentdisclosure. For example, the flanges may comprise a plurality ofprotruding stent elements that respectively comprise individual wires orbundled sets of wires. The plurality of wires may comprise a regularlyor irregularly spaced array, and the wires themselves may be present assingle strands, or as grouped or bundled sets of two, three, four, ormore wire strands. In other embodiments, the flanges may comprise aplurality of wire loops. The wire loops may be integral with the wireframework of the stent. For example, the stent may comprise wire weavethat defines (in addition to the other elements of the stent) flangesthat comprise a plurality of wire loops. The wire loops may comprise aregularly or irregularly spaced array.

Each flange may have a configuration that corresponds to the unexpandedstate of the stent, and a configuration that corresponds to the expandedstate of the stent. For example, when one or both of the flangescomprise a plurality of individual stent wires, the elements may besubstantially straightened when the stent is in the unexpanded state andmay be substantially coiled when the stent is in the unexpanded state.In other instances, a flange may comprise one or more elements thatdefine flaps, lobes, loops, or other projections that may be orientedsubstantially parallel with the long axis of the stent when the stent isin an unexpanded state and are differently oriented when the stent is inan expanded state. Some embodiments are such that the upper flange andlower flange each comprise a plurality of protruding stent elements thatare each substantially straightened when the stent is in the unexpandedstate and are each substantially bent back towards the middle region ofthe stent when the stent is in the expanded state.

It has presently been discovered that a stent that comprises a loweranchoring flange having at least one geometric dimension that is greaterthan the corresponding dimension of the upper anchoring flange iscapable of reliably adhering the prosthesis to the site of implantation.Traditionally, replacement of damaged or diseased valves consisted ofthe removal of the defunct valve tissue in order to clear a space forthe prosthetic valve apparatus and avoid unwanted interference with thefunctioning of the prosthesis. The present design does not require theremoval of defunct valve tissue, and in fact benefits from the presenceof such tissue, because it is capable of grasping the tissue that ispresent at the site of implantation (whether such tissue comprisesdefunct valve material or otherwise) by virtue of the lower anchoringflange, and is capable of similar grasping, as well as “capping”, byvirtue of the upper anchoring flange. For example, when the site ofimplantation is the mitral valve annulus, the inventive prosthesissecurely adheres to the site of implantation because, inter alia, of theaction of lower anchoring flange to grasp the defunct valve tissue andannulus tissue on the ventricular side, and of the action of the upperanchoring flange to grasp such tissue and likewise provide a “cap” onthe atrial side of the annulus.

As used herein, the terms “lower” and “upper” are merely terms ofconvenience; a prosthesis for implantation in a mitral valve annulus,for example, will be positioned in situ such that the “lower” anchoringflange is oriented on the ventricular side of the annulus and therebysubstantially “downwards”, and the convention therefore arose to use theterm “lower” to designate the ventricular-side flange, which possesses ageometric dimension that is greater than the corresponding dimension onthe upper flange. In general, because the use of the terms “upper” and“lower” are merely conventions, there is no requirement for the “lower”anchoring flange to be oriented substantially or even partially“downwards” when the prosthesis is used in other contexts.

The geometric dimension that is greater in the lower anchoring flange ascompared with the upper anchoring flange may be any dimension that isshared by the respective flanges. Thus, the geometric dimension may belength, width, height, or any other parameter. In one example, the loweranchoring flange comprises a plurality of protruding stent elements ofequal length, wherein the protruding stent elements of the loweranchoring flange are longer than a series of protruding stent elementsthat form the upper anchoring flange. When the upper and lower anchoringflange respectively comprise a plurality of protruding stent elements,the lower anchoring flange may be said to have a geometric dimensionthat is greater than the corresponding dimension of the upper anchoringflange when more than 50%, more than 60%, more than 70%, more than 75%,more than 80%, more than 85%, more than 90%, more than 95%, or 100% ofthe protruding stent elements of the lower flange have a greaterdimension than the protruding stent elements of the upper flange.

FIG. 5 provides views of an exemplary stent 21 of this variety, havingan upper flange 22 and a lower flange 24 of which each comprises aplurality of protruding stent elements 26. Protruding stent elements 26are substantially straightened and oriented substantially parallel withthe long axis Y when stent 21 is in an unexpanded state (FIG. 5A) andthat are substantially bent back towards the middle region 28 when stent21 is in the expanded state (FIG. 5B). The stent 21 of FIG. 5B isvertically inverted relative to that of FIG. 5A, i.e., the upper flange22 in FIG. 5B appears at the bottom of the drawing of stent 21, ratherthan at the top portion (as in FIG. 5A). The protruding stent elements26 of the lower flange 24 are longer than the protruding stent elements26 of the upper flange 22. When the stent 21 is in an expanded state,the protruding stent elements 26 exert a force in the direction of thestent body, such that any material that is interposed between aprotruding element 26 and the outer surface of the middle region of thestent 28 will be trapped between the two elements. Accordingly, when aprosthesis comprising a stent such as that described herein is deliveredto an implantation site and shifts from its unexpanded state to itsexpanded state, loose tissue at the implantation site, such as defunctvalve tissue, will be ensnared between the respective flanges and themiddle region of the stent. This action significantly contributes to theanchoring of the prosthesis to the site of implantation. Example 2,below, discloses the measurement of the force that was required toextract an exemplary valve prosthesis according to the presentdisclosure from a site at which the prosethesis had been implanted.

FIG. 5B denotes various dimensions of exemplary stent 21 in its expandedstate. Line a designates the diameter of stent 21; line b indicates thelength of the individual protruding stent elements 26 of the lowerflange 24; line c designates the height of stent 21, including thecontribution of the upper and lower flange elements 22, 24; line drefers to the height of middle region 28; line e) points to the diameterof the lower flange elements 24 that are bent back towards middle region28; and, line f) designates the diameter of the upper flange elements 22that are bent back towards middle region 28.

The diameter of the stent in its expanded state may be, for example,about 25 to about 55 mm. The length of an individual protruding stentelement of a lower flange may be, for example, about 5 to about 45 mm.The height of the stent in its expanded state (i.e., the dimensionrunning parallel to the stent lumen—designated by line c in FIG. 5B),including the contribution of the upper and lower flange elements, maybe, for example, from about 15 to about 55 mm. The height of the middleregion alone when the stent is in its expanded state may be, forexample, about 15 to 45 mm. The diameter of the lower flange elementsthat are bent back towards the middle region (as designated by line e inFIG. 5B) may be, for example, about 1 to about 8 mm. The diameter of theupper flange elements that are bent back towards the middle region ofthe stent (as designated by line fin FIG. 5B) may be, for example, about3 to about 12 mm.

With respect to the compressed stent shown in FIG. 5A, the total lengthof the stent may be from about 4 to about 15 cm, and the width of thecompressed stent at the middle region 28 may be about 5 to about 15 mm,preferably about 6 to about 12 mm.

As indicated above, the amount of outward radial force that is exertedby the stent is influenced by, inter alia, the density of the wireframework. In general, a higher density results in the exertion of agreater outward radial force. FIG. 6 provides an illustrative example ofhow to characterize wire weave density, as well as how wire weavedensity and wire thickness respectively affect various parameters of theinventive stent 21. The process of constructing a wire weave maydescribed in terms of “steps” and “step-overs”.

FIG. 6A shows one embodiment of an inventive stent 21 comprising wireweave that includes an upper flange 22 comprising thirty-one individualprotruding stent elements and a lower flange 24 comprising thirty-oneindividual protruding stent elements. With respect to the embodimentshown in FIG. 6A, each individual protruding stent element 26constitutes a “step” in the construction process, and each “step”requires 5 “step-overs” to form the body of the stent 21.

FIG. 6B shows a further embodiment of an inventive stent 21 comprisingwire weave that includes an upper flange 22 comprising twenty-fiveindividual protruding stent elements and a lower flange 24 comprisingtwenty-five individual protruding stent elements. For the embodiment ofFIG. 6B, each individual protruding stent element 26 constitutes a“step” in the construction process, and each “step” requires 3“step-overs” to form the body of the stent 21.

The number of “step-overs” that may be used to form a stent comprisingwire weave according to the present invention can be 2, 3, 4, 5, 6, 7,8, 9, or 10.

FIGS. 6A and 6B also illustrate how the thickness of the wire that isused to form a stent 21 comprising wire weave can influence certaincharacteristics of the stent. The embodiment of FIG. 6A involves the useof wire having a thickness of 0.025 inches, whereas the embodiment ofFIG. 6B involves the use of wire having a thickness of 0.012 inches. Theterminal bend of each individual protruding stent element 26 is wider inthe case of the embodiment of FIG. 6A as compared with the correspondingelements of FIG. 6B, because thicker wire is used in the case of theformer than in the latter. As indicated previously, the thickness of thewire that is used to form the framework of an inventive stent may beabout 0.005 inches to about 0.030 inches.

The present valve prostheses may also comprise a cuff comprising anabsorbent material that is disposed at least partially circumferentiallyaround the outer surface of the stent. The term “cuff” is intended toembrace a continuous ring of absorbent material that forms a completecircle around the outer surface of the stent; any other conformationthat involves a contiguous portion of absorbent material, such as astrip that forms a spiral around the outer surface of the stent; one,two, three or more disparate patches or strips (or any other shape orconfiguration) of absorbent material disposed on the outer surface ofthe stent; or, any combination of one or more contiguous portions ofmaterial and disparate patches, strips, and the like. In a preferredembodiment, the cuff comprises a continuous ring of absorbent materialthat forms a complete circle around the outer surface of the stent.

When present, the cuff comprises an absorbent material that expands byabsorption of a fluid to substantially adhere the prosthesis at theimplantation site. When the disclosed prostheses are used to replace adamaged or nonfunctional mitral valve, the implantation site is themitral valve annulus. As used herein to “adhere” may mean tosubstantially affix or anchor the prosthesis at the implantation site,to create a seal between the cuff and the mitral valve annulus that issubstantially impermeable to fluid, or both. It has been presentlydiscovered that the cuff can form a seal that reliably preventsperivalvular leakage between the atrium and ventricle, such that whenthe prosthesis is in place, the only fluid that passes between theatrium and ventricle is that which is allowed to pass by the activity ofthe replacement valve itself.

In embodiments that include a cuff, the adhering of the prosthesis isdelayed for a time sufficient to permit positioning of the prosthesis atthe implantation site. For example, because the procedure forpositioning the prosthesis via a catheter at the implantation site maylast 40 minutes, the expansion by the cuff by absorption of fluid to asufficient degree such as to adhere the prosthesis to the implantationmay be delayed until that time has elapsed. Thus, the cuff comprises oneor more materials, components, or both that creates a delay in theabsorption of fluid or that provides a sufficiently slow rate ofabsorption of the fluid, such that the cuff does not expand to thedegree required to adhere the prosthesis to the implantation site untilthe desired period of delay has elapsed. The period of delay may bemeasured starting at the point in time where the prosthesis is exposedto a fluid (e.g., blood). The delay period may be about 1 minute, about2 minutes, about 5 minutes, about 7 minutes, about 10 minutes, about 15minutes, about 20 minutes, about 30 minutes, about 45 minutes, about 1hour, about 75 minutes, about 90 minutes, or about 2 hours. The type ofcuff that is selected for use with the prosthesis may depend on thedifficulty of the procedure to deliver the prosthesis to theimplantation site.

The absorbent material of the cuff may itself absorb fluid at asufficiently slow rate to delay the adhering of the prosthesis at theimplantation site. In other embodiments, the absorbent material of thecuff may feature a variable rate of absorption, such that the rate ofabsorption is low for an initial period of time but that increases overtime or after a period of time. For example, the absorbent material mayhave a fluid absorption rate of about 0 μL to about 20 μL per minute fora first period of time following exposure of the prosthesis to thefluid, and a fluid absorption rate from about 10 to about 200 μL perminute after the first period of time. The period of time after whichthe rate of absorption increases may be about 10 minutes, about 15minutes, about 20 minutes, about 30 minutes, about 45 minutes, about 1hour, about 90 minutes, about 2 hours, about 180 minutes, or about 2hours. In other embodiments, the ability of the absorbent material ofthe cuff to absorb fluid is delayed. For example, the absorbent materialof the cuff may be completely or partially covered with or containedwithin a material that affects the ability of the absorbent material toabsorb fluid. The absorbent material may be completely or partiallycovered with or contained within a cover material, e.g., a film orfabric, that is permanently impermeable to fluid, but that is removableand is removed when the desired period of delay has elapsed; the removalof the cover material may be effected while the prosthesis is in situ atthe implantation site, for example, by using a catheter-based removaltool to grasp and remove the cover material. Any material that issubstantially impermeable to fluid (such as water, blood, and the like)and that is biocompatible may be used to form the cover material.Nonlimiting examples include polyurethanes, polyethylenes,polydimethylsiloxane, silicones, rubbers, and polyvinyl chloride. Inother embodiments, the absorbent material may be completely or partiallycovered with or contained within a cover material, e.g., a film orfabric, that is temporarily impermeable to fluid, but that becomespermeable to fluid after a desired period of delay. For example, thecover material may be degradable over time, or may comprise a materialthat degrades or is altered in response to a change in temperature, pH,or some other environmental cue that is present at the implantationsite. In other embodiments, the absorbent material may be completely orpartially covered with or contained within a cover material that ispermeable to fluid, but the transfer of fluid across such cover materialand/or saturation of by the cover material by fluid is sufficiently slowto provide a delay before the absorbent material absorbs a sufficientamount of fluid to adhere to the implantation site. The period of delaythat is provided by a cover material may be, for example, about 5minutes to about 3 hours, about 10 minutes to about 3 hours, about 20minutes to about 2 hours, about 30 minutes to about 2 hours, about 45minute to about 90 minutes, or about one hour following exposure of theprosthesis to a fluid. In still other embodiments, the ability of theabsorbent material of the cuff to absorb is delayed because theabsorbent material itself or a material that is mixed in or otherwisesubstantially interspersed or integrated with the absorbent material isaltered in response to one or more conditions (e.g., temperature, pH,and the like) that are present at the implantation site. For example,the absorbent material may include or may be provided along with apolymer that changes shape over time in response to exposure to thefluid or some other environmental cue present at the implantation site,and such shape change permits the initiation or the acceleration of theabsorption of fluid by the absorbent material.

Exemplary substances that may be used to form the absorbent materialinclude any crosslinked hydrogel component. A crosslinked hydrogelcomponent may be based on covalent crosslinks, physical/ioniccrosslinking, or both. Nonlimiting examples include poly(acrylic acid),poly(ethylene glycol), poly(ethylene oxide), poly(propylene oxide),poly(vinyl alcohol), polyvinyl pyrrolidinone, poly(hydroxy ethylmethacrylate), poly(amino acids), Dextran, polysaccharides, andproteins. Further examples of substances that may be used to form theabsorbent material include sodium polyacrylate, polyacrylamidecopolymer, ethylene maleic anhydride copolymer, carboxy-methyl-cellulosepolyvinyl alcohol copolymers, polyethylene oxide, and polyacrylonitrile.

Any “super absorbent” material, for example, a super absorbent polymer,also may be used in the cuff, when present. As used herein, a “superabsorbent” material is one that features an increase in volume swellingratio (Qv; swollen volume divided by “dry” volume or volume before anyfluid has been absorbed) from 1 to about 5-1000. Some examples of superabsorbent materials are listed above. Those of ordinary skill in the artcan readily identify other suitable materials that may be characterizedas “super absorbent” and any such material may be used. Preferably, thecuff is configured so that expansion occurs predominantly in a singledirection. For example, the expansion may predominantly in a directionthat is substantially perpendicular relative to the outer surface of thestent. If the cuff comprises a continuous ring of absorbent materialthat forms a complete circle around the outer surface of the stent, thedirection of expansion of the absorbent material may be characterized asradial. Because the stent in its expanded state will be sufficientlyrigid to resist compression as a result of any radial expansion by theabsorbent material in the direction towards the surface of the stent,the radial expansion of the absorbent material will be substantiallyunidirectional in the direction away from the surface of the stent,i.e., towards the interior surface of the mitral valve annulus. Asdescribed above, the expansion of the absorbent material can enhance theseal between the cuff and the valve annulus that prevents perivalvularleakage.

A prosthesis according to the present disclosure may further comprise awebbing that is disposed at the upper flange, lower flange, or both. Thewebbing may comprise an absorbent material. The presence of the webbingmay assist with the adhering (i.e., the affixing, anchoring, and/orsealing) of the prosthesis at the implantation site. Accordingly, thewebbing may expand by absorption of a fluid, and the resulting adheringmay be delayed for a time sufficient to permit positioning of theprosthesis at the implantation site. When one or both of the upper andlower flanges comprise discrete elements, such as protruding stentelements as described above, a portion of the webbing may be disposedbetween at least one pair of the protruding stent elements of either orboth of the flanges. Preferably, the webbing is disposed between aplurality of pairs of protruding stent elements of the upper anchoringflange and between a plurality of pairs of protruding stent elements ofthe lower anchoring flange. When one or both of the upper and lowerflanges comprise flaps, lobes, loops, or other projections, part or allof each of the projections may be fitted with webbing. Each of thecharacteristics of the materials or components that are described abovewith respect to the cuff may be present in the webbing. Thus, thewebbing the may comprise one or more materials, components, or both thatcreates a delay in the absorption of fluid or that provides asufficiently slow rate of absorption of the fluid, such that the webbingdoes not expand to the degree required to adhere the prosthesis to theimplantation site until the desired period of delay has elapsed.

The prostheses of the invention also comprise a valve comprising atleast one leaflet that is fixedly attached to the interior surface ofthe stent. The attachment of the leaflet or leaflets to the interiorsurface of the stent need not be direct; for example, a valve supportring may be fixedly attached to the interior surface of the stent, andthe valve(s) may be fixedly attached to the valve support ring. Thevalve may comprise one leaflet, two leaflet, or three leaflets. Theleaflets are preferably derived from a biological source, such asmammalian pericardium. For example, the leaflets may be made frombovine, equine, ovine, caprine, or porcine pericardium. In otherembodiments, the leaflets may be derived from animal valves, preferablymammalian valves. Nonlimiting examples include bovine jugular veinvalves, porcine pulmonary valves, and porcine aortic valves. Those ofordinary skill in the art will appreciate how to select the appropriatevalve for the desired purpose. For example, it will be recognized thatthe suitability of a particular type of valve and number of leaflets maybe affected by the intended use of the valve prosthesis. In oneinstance, the intended use of the valve prosthesis may be thereplacement of a damaged or diseased mitral valve, in which case itwould be appreciated that a three-leaflet valve should be selected. Theinstant prostheses may be configured for replacing any cardiac valve,such as the pulmonary valve, the tricuspid valve, the aortic valve, orthe mitral valve.

The present disclosure also includes methods for replacing a damaged ordiseased valve in a subject comprising: delivering to an implantationsite of the subject a valve prosthesis comprising an at least partiallyself-expanding stent comprising a wire framework defining outer andinterior surfaces, and upper and lower anchoring flanges interposed by amiddle region, the stent having an unexpanded and an expanded state, andthe lower anchoring flange having at least one geometric dimension thatis greater than the corresponding dimension of the upper anchoringflange; and a valve comprising at least one leaflet fixedly attached tothe interior surface of the stent; and expanding the stent tosubstantially adhere the prosthesis at the implantation site.

Each of the attributes, components, materials, and the like that aredescribed above with respect to the inventive valve prostheses may beused in accordance with the present methods.

Delivery of the valve prosthesis to an implantation site may beaccomplished transatrially, transapically, or percutaneously. Deliveryof the prosthesis may be followed by one or more positioning steps(i.e., positioning and, if desired, repositioning), whereby the locationof the prosthesis may be adjusted for optimal positioning in relation tothe valve annulus.

For transatrial delivery, an exemplary procedure may be performed asfollows. A small (2-3 cm) thoracotomy through the inter costal space ismade. The inter-atrial plane is developed. The right atrium isretracted, and a purse string suture is placed in the left atrium. Then,a steerable introducer catheter is placed into the left atrium throughthe purse string. The catheter is advanced through the mitral valveannulus. Its position may be guided and confirmed by echocardiography.The prosthesis is introduced through the catheter. The lower(ventricular) flange expands first and anchors to the ventricular sideof the annulus and the subvalvular apparatus (leaflets, chordea, leftventricular wall). The remainder of the stent and upper (atrial) flangeare delivered, also under echocardiographic guidance. The atrial flangeexpands and anchors to the annulus and left atrium. In embodiments ofthe prosthesis that include a cuff, the sealing cuff remains flaccidduring the ensuing 60 minutes to allow documentation by echocardiographythat the valve's position and function are adequate. After an hour inplace the cuff fully expands to seal the device against the nativemitral valve annulus.

For transapical delivery, an exemplary procedure may be performed asfollows. A small left thoracotomy is performed—similar in size to thatwhich is used during the transatrial delivery procedure. A purse stringsuture is place in the left ventricular apex. A steerable catheterintroducer is then placed into the left ventricle through the pursestring. The introducer catheter is guided through the mitral valveannulus into the left atrium under echocardiographic guidance. For thisapproach, the device may be designed so that the atrial flange isdeployed and positioned first. The optional cuff and/or webbing may besimilar to that described above with respect to the exemplarytransatrial delivery process.

Percutaneous delivery may be venous or arterial. When percutaneousdelivery is the intended procedure, the prosthesis is configuredaccordingly, e.g., foldable enough to be placed via peripheral venous orarterial access.

Venous percutaneous delivery may be performed as follows. Access to thefemoral vein is achieved by standard techniques that will be readilyappreciated by those skilled in the art. A steerable catheter is thenintroduced into the venous system and guided to the right atrium usingfluoroscopic guidance. Once in the right atrium, standard techniques areused to traverse the catheter across the intra-atrial septum to the leftatrium. The prosthesis is then deployed under echocardiographic guidanceas described in the transatrial approach.

For aterial percutaneous delivery, an exemplary procedure may beperformed as follows. Access to the femoral artery is achieved bystandard techniques. A steerable catheter is then introduced into thearterial system and guided to the aortic root and into the leftventricle using fluoroscopic guidance. Once in the left ventricle thedevice is deployed as described above in connection the transapicalapproach.

In another aspect, provided are systems for delivering a valveprosthesis comprising an at least partially self-expanding stent to animplantation site comprising: a catheter comprising a distal end and aproximal end, a guidewire lumen to permit the catheter to be translatedalong a guidewire, a steering lumen for accommodating a tension cablefor steering the catheter, and a dock at the distal end onto which thestent may be loaded. The present systems also comprise a retractablecompression sleeve for compressing at least a portion of the stent whilethe stent is loaded onto the dock; a leading tip positioned distal tothe dock for leading the catheter during delivery; and, a steeringmechanism operably associated with the tension cable for deflecting theleading tip in at least one directional plane.

Unlike existing delivery systems, the disclosed systems are capable ofhousing, transporting, and delivering stents of valve prosthesesaccording to the present disclosure, as well as stents of otherconfigurations, including conventional stented devices. As will bediscussed more fully herein, the present systems include a number offeatures that address certain challenges that are associated with themanipulation and implantation of at least partially self-expandingstents, including those having the characteristics of the stents thatare used with the presently disclosed prostheses.

The catheter of the present system includes a distal end, which is theend of the catheter that is first introduced into the physiologicalpoint of entry during the stent implantation procedure. The proximal endof the catheter (defined herein as the end of the catheter that isclosest to the operator of the system during use) remains outside of thesubject. The instant catheters may have a length of about 20 cm to about200 cm from the distal end to the proximal end. The outer diameter ofthe catheter may be about 0.5 cm to about 1.5 cm.

The catheter may be constructed from any suitable material, whereinsuitability is determined by such considerations as biologicalcompatibility, durability, the appropriate balance between rigidity andflexibility, and other readily appreciable factors based on the intendeduse of the catheter. For example, polyimide, polyethylene,polypropylene, Kalrez®, Simriz®, Viton®, Chemraz®, silicone, neoprene,nitrile, metal or metal alloys (such as Ti—Nb—Zr; see, e.g., U.S. Pat.No. 5,685,306) or any other combination thereof may be used. Thematerials used for the construction of the catheter, as well as themethods for the construction thereof, are readily appreciated by thoseskilled in the art, and all appropriate materials and means ofconstruction are contemplated herein.

The catheter includes at least two lumens, the first being a guidewirelumen to permit the catheter to be translated along a guidewire, thesecond being a steering lumen for accommodating a tension cable forsteering the catheter. The guidewire lumen is appropriately sized,shaped, and located within the catheter to accommodate a guidewire, suchthat the catheter may be translated over a guidewire that has beenplaced along the appropriate physiological pathway to a site of interestwithin a subject. The steering lumen is appropriately sized, shaped, andlocated within the catheter to accommodate a tension cable. Themanipulation of a tension cable that is located within a lumen of thepresent catheters causes the deflection of the catheter, which in turnallows the catheter to be moved from a first location to a secondlocation in situ. The selection and use of guidewires and steeringtension cables are well known among those skilled in the art. There areno limitations on the relative arrangement of the lumens within thecatheter. However, it is traditional for a guidewire lumen to be locatedtowards the center of a catheter. In one embodiment, the guidewire lumenand the steering lumen are provided in a side-by-side arrangement withinthe catheter. In other instances, the guidewire lumen may be locatedsubstantially in the center of the catheter, and the steering lumen islocated between the guidewire lumen and the outer surface of thecatheter. It may be desirable to include more than one steering lumen,wherein each steering lumen may accommodate a separate tension cable, inorder to enhance the steerability of the catheter. For example, anexemplary catheter may include a single guidewire lumen and two, three,or four separate steering lumens.

The catheters of the present systems further comprise a dock at thedistal end of the catheter onto which a stent may be loaded. The dock ispreferably integral with the rest of the catheter, and may simplycomprise a distal portion of the catheter having a smaller diameter thanthe remainder of the catheter, or at least of the portion of thecatheter that is located immediately adjacent to the dock. For example,whereas the outer diameter of the catheter (excluding the dock) may beabout 0.25 cm to about 1.5 cm, the outer diameter of the dock may befrom about 25% to about 75% of the diameter of the remainder of thecatheter. Stated in absolute terms, the outer diameter of the dock maybe about 0.10 cm to about 0.80 cm. The length of the dock is preferablyat least as long as a stent in its fully compressed state (of whichexemplary lengths are provided above in connection with the presentlydisclosed prostheses), and may be somewhat longer than a compressedstent. Stated in absolute terms, the length of the dock may be fromabout 4 cm to about 15 cm.

The dock may optionally comprise an inflatable balloon for expanding orassisting with the expansion of a stent that is loaded onto the dock.The use of inflatable balloons for the expansion of stents is well knownamong skilled artisans. Because such balloons are typically actuated ata desired time via the selective induction of fluid (liquid or gas)pressure, when the dock comprises an inflatable balloon, the cathetermay further comprise a balloon lumen for supplying the fluid (forexample, saline, water, or CO₂ gas) that is used to inflate the balloon.When inflated, the balloon may adopt any configuration that is suitablefor assisting with the expansion of the stent; for example, the inflatedballoon may be an elongated torus or a series of two or more tori thatare distributed along the length of the dock.

The present systems further comprise at least one retractablecompression sleeve for compressing at least a portion of the stent whilethe stent is loaded onto the dock. The compression sleeve is preferablyin coaxial arrangement with the catheter, for example, functioning likea cannula or outer covering that translates over the catheter in adirection that is towards or away from the catheter's distal end. Astent may be loaded onto the dock in a compressed state, and thecompression sleeve may be translated over the dock so that it passesover and encircles the compressed stent; in this way, the compressionsleeve ensures that the stent remains compressed while loaded onto thedock. Specialized techniques may be required to load the stent onto thedock in a compressed state. With the compressed stent loaded onto thedock and at least one compression sleeve in coaxial arrangement with thedock and ensuring that the stent remains compressed, the distal end ofthe catheter may be delivered to the site of implantation, where thecompression sleeve is eventually withdrawn and the stent therebypermitted to expand at the implantation site.

A compression sleeve may be made from any material that is biocompatibleand is capable of functioning in the described manner. For example, acompression sleeve may be constructed from a rigid material so that itis not damaged or distorted by the outward radial force that is exertedby the compressed stent. The interior and/or exterior surfaces of thecompression sleeve are preferably configured to result in a lowcoefficient of friction against any other component or physiologicalfeature against which the sleeve may slide during use; this feature maybe inherent in the material from which the sleeve is constructed, or maybe imparted to the sleeve material by a low-friction coating. Oneexemplary material for use in constructing the compression sleeve ispolytetrafluoroethylene (PTFE—sometimes produced under the trade nameTeflon®). Any other suitable materials may be used, optionally coated onone or both of the inside and outside surfaces with PTFE or anothermaterial that is suitable for reducing friction.

A single compression sleeve may be used to compress the entire stent. Inother instances, the system may comprise two or more compressionsleeves; a second retractable compression sleeve, or other furthercompression sleeves, may be present for compressing a further portion ofthe stent when the stent is loaded onto the dock. For example, a firstcompression sleeve may be present and used to keep the middle region ofthe stent in the compressed state, and a second compression sleeve maybe used to keep the upper and lower flanges of the stent in thecompressed state. In such embodiments, when the stent is loaded onto thedock, both the first and second compression sleeves are positioned incoaxial arrangement with the dock, with the first compression sleevebeing positioned directly over the stent, and the second compressionsleeve being positioned over the first compression sleeve and the stent;withdrawal of second compression sleeve (e.g., by translation over thecatheter in the direction away from the dock) results in the expansionof the flanges, and subsequent withdrawal of the first compressionsleeve results in the expansion of the remainder of the stent. Becauseof the nature of the process of withdrawing the second compressionsleeve, either the upper or lower flange will expand prior to theexpansion of the other of the upper and lower flanges. The precedingprocess is described more fully below in connection with FIGS. 7-9.Expansion of the flanges by removal of the second compression sleeveprior to the expansion of the middle region by removal of the firstcompression sleeve results in the deployment of the flanges at theimplantation site, which allows the stent to at least partially adhereto the implantation site before the middle region of the stent(containing the valve) is deployed.

The present systems further comprise a leading tip that is positioneddistal to the dock portion of the catheter and that is for leading thecatheter during the delivery process. The leading tip may besubstantially conical, may be rounded at its distal end, or may have anyother configuration that enhances the ease with which the tip andthereby the trailing catheter are directed through a subject'svasculature. Materials that may be used to form the leading tip mayinclude any rigid, biocompatible, and preferably low-friction material.Examples include nylon, silastic, plastic, nitinol, stainless steel,cobalt/chromium alloy, cobalt/chromium/nickel alloy, nickel/chromiumalloy, platinum, and platinum/iridium alloy. The leading tip may besecurely yet removably attachable to the distal end of the dock, so thatthe stent can be loaded onto the dock prior to the attachment of theleading tip.

The systems according to the present disclosure also comprise a steeringmechanism that is operably associated with the tension cable or cablesand that is for deflecting the leading tip in at least one directionalplane. The association between the steering mechanism and the tensioncable or cables is described as operable because the steering mechanismmakes use of its connection to the tension cable to deflect the leadingtip. The use of tension cables for the deflection of a tension cablehousing is readily understood among those skilled in the art. Thesteering mechanism may be any device that allows a user to manipulatethe tension cable(s) and thereby the catheter in the intended manner—forexample, an obturator knob, lever, dial, or any appropriate mechanismmay be used. The deflection of the leading tip by use of the steeringmechanism permits both the guidance of the catheter through a subject'svasculature (for example, to effect the downturn into the subject'sventricle) and the precision placement of the dock and stent at or nearthe site of implantation. The steering mechanism is typically used inconjunction with an appropriate imaging technology, such as fluoroscopyor echocardiography.

In yet another aspect, there are disclosed kits comprising a systemcomprising an at least partially self-expanding stent to an implantationsite comprising: a catheter comprising a distal end and a proximal end;a guidewire lumen to permit the catheter to be translated along aguidewire; a steering lumen for accommodating a tension cable forsteering the catheter; a dock at the distal end onto which the stent maybe loaded; a retractable compression sleeve for compressing at least aportion of the stent while the stent is loaded onto the dock; a leadingtip positioned distal to the dock for leading the catheter duringdelivery; and, a steering mechanism operably associated with the tensioncable for deflecting the leading tip in at least one directional plane;and, at least one valve prosthesis comprising an at least partiallyself-expanding stent comprising a wire framework defining outer andinterior surfaces, and upper and lower anchoring flanges interposed by amiddle region, the stent having an unexpanded and an expanded state, andthe lower anchoring flange having at least one geometric dimension thatis greater than the corresponding dimension of the upper anchoringflange; and a valve comprising at least one leaflet fixedly attached tothe interior surface of the stent.

Each of the attributes, components, materials, and the like that aredescribed above with respect to the inventive valve prostheses andsystems may be used in accordance with the prostheses and systems,respectively, that are included in the present kits.

The kits may further comprise one or more of the following additionalcomponents: instructions for use; replacement parts for any of thecomponents of the system or prosthesis; and, tools for the repair of thesystem. In certain embodiments, the present kits comprise a plurality ofvalve prostheses, wherein the diameter of at least one of the prosthesesin its expanded state is greater than the diameter of at least one otherof the prostheses in its expanded state. Such embodiments account forthe fact that user must choose a valve prosthesis that that is suitablysized in its expanded state for implantation in the particular site ofinterest within the particular patient at hand. The inner diameter ofvalve annuli vary within a particular patient, such that, for example,the diameter of the aortic valve annulus may be different from thediameter of the mitral valve annulus. Likewise, the inner diameter of aparticular valve annulus, such as the mitral valve annulus, may varyfrom patient to patient, such that a first patient has a mitral valveannulus with a greater diameter than that of the mitral valve annulus ofa second patient. Thus, a valve prosthesis must be selected to possessan appropriate diameter in its expanded state, wherein the propriety ofa particular expanded diameter depends on the intended site ofimplantation and on the particular subject. It is therefore advantageousto include within a kit of the present disclosure at least twoprostheses, wherein the diameter of at least one of the prostheses inits expanded state is greater than the diameter of at least one other ofthe prostheses in its expanded state, so that a choice may be made,depending on the relevant criteria, from among at least two different“sizes” of prosethesis.

The present kits may include at least two prostheses of which onepossesses a different type of valve than at least one other prosthesis.For example, a particular kit may include three valve prostheses, ofwhich two include a replacement mitral valve, and one includes areplacement aortic valve. The systems that are described herein forinclusion in the present kits may be used to deliver any type ofprosthesis (including a prosthesis comprising any type of valve) to asite of implantation, and the inclusion of prostheses that respectivelyinclude different types of valves enables the user to select theprosthesis that is most suitable for the intended purpose.

FIG. 7 depicts the components of an exemplary kit according to thepresent disclosure. As shown in FIG. 7D, the kit comprises system thatincludes a catheter 30 that has a distal end 32 and a proximal end 34.FIG. 7A provides a cross-sectional view of catheter 30 that reveals theguidewire lumen 36 and three steering lumens 38. Returning to FIG. 7D,dock 40 is at distal end 32 of catheter 30, and leading tip 42 ispositioned distal to the dock 40. During use of the system, a prosthesiswill be loaded onto dock 40. Steering mechanism 44 is located atproximal end 34 of catheter 30 and, in the depicted embodiment,comprises an obturator knob 46. The kit also includes a prosthesiscomprising a stent 21 that comprises a wire framework, shown in itsexpanded state in FIG. 7B and in its compressed state in FIG. 7C. Thewire framework of stent 21 defines upper 22 and lower 24 flangesinterposed by a middle region 28. A valve 29 is fixedly attached to theinterior of the stent 21.

The present disclosure also pertains to methods for delivering a valveprosthesis comprising an at least partially self-expanding stent to animplantation site comprising: (i) providing a system comprising acatheter comprising a distal end and a proximal end; a guidewire lumento permit the catheter to be translated along a guidewire; a steeringlumen for accommodating a tension cable for steering the catheter; adock at the distal end onto which the stent may be loaded; a retractablecompression sleeve for compressing at least a portion of the stent whilethe stent is loaded onto the dock; a leading tip positioned distal tothe dock for leading the catheter during delivery; and, a steeringmechanism operably associated with the tension cable for deflecting theleading tip in at least one directional plane; (ii) loading onto thedock the valve prosthesis; (iii) delivering a guidewire to theimplantation site; (iv) translating the catheter over the guidewire sothat the loaded valve prosthesis is positioned at the implantation site;(v) retracting the retractable compression sleeve to permit the stent toexpand at the implantation site and to undock from the catheter; and,(vi) removing the catheter and the guidewire from the implantation site.

Each of the attributes, components, materials, and the like that aredescribed above with respect to the inventive valve prostheses andsystems may be used in accordance with the prostheses and systems,respectively, that are used in accordance with the present methods.

FIGS. 8-9 illustrate an example of how retractable compression sleeves48, 50 may be used to compress a stent 21 against the dock 40 of acatheter 30 during delivery to an implantation site, and to permit thestent to expand at the implantation site and undock from the catheter30. FIG. 8A depicts a compressed stent 21 that is mounted on dock 40 ofa catheter 30; for simplicity, no compression sleeves are shown, eventhough the absence of a compression sleeve would ordinarily allow thestent 21 to expand. FIG. 8B shows how a first compression sleeve 48,shown as a dark gray layer (see illustrative inset X), is advanced overstent 21 and functions to compress the middle region 28 of stent 21.Lower flange 24 is not covered by first compression sleeve 48. In FIG.8C, a second compression sleeve 50, shown as a lighter gray layer (seeillustrative inset Y) is advanced over both first compression sleeve 48and stent 21, this time including lower flange 24 of stent 21. Secondcompression sleeve 50 therefore ensures that lower flange 24 remainscompressed during delivery of the distal end of catheter 30 to animplantation site.

FIG. 9A-C depicts in reverse order how the withdrawal of compressionsleeves allows a prosthesis comprising a stent to expand in acontrolled, sequential manner. In FIG. 9C, a first compression sleeve 48and a second compression sleeve 50 are in place in coaxial arrangementover a stent that is mounted on the dock 40 of catheter 30; in concert,compression sleeves 48, 50 compress the middle region 28 of the stentand the flanges 22, 24 such that the stent remains mounted on dock 40.The light gray arrows in FIG. 9C indicate the direction in which secondcompression sleeve 50 is withdrawn over catheter 30 in order to proceedto the next step of the process of expanding the stent at theimplantation site. FIG. 9B shows the results of withdrawing secondcompression sleeve 50: lower flange 24 has commenced to expand. Thedarker gray arrows in FIG. 9B indicate the direction in which firstcompression sleeve 48 is withdrawn over catheter 30 in order to permitexpansion of each of the components of the stent. In FIG. 9A, firstcompression sleeve 48 has been fully withdrawn, and each of the lowerflange 24, upper flange 22, and middle region 28 of the stent 21 havefully expanded. Lower flange 24 is bent back towards middle region 28,and any tissue that is interposed between these to components will besecurely clamped.

In some embodiments of the present methods, the dock of the catheter maycomprise an inflatable balloon, and following retraction of aretractable compression sleeve, the method may further comprise at leastpartially inflating the balloon to further expand the stent. Althoughthe stent is at least partially self-expanding, it may be desireable touse a balloon to ensure that the stent reaches its maximally expandedstate.

FIG. 10 illustrates how the process described in FIG. 9 will result inthe implantation in situ of a valve prosthesis that comprises a wireframework. In FIG. 10A, the implantation process is shown at the pointwhere catheter 30 had been advanced to the implantation site (the mitralvalve annulus), with leading tip 42 having been advanced past the valveannulus into the ventricle, and the dock, loaded with a compressed valveprosthesis, having been positioned within the valve annulus. FIG. 10Bshows how the initial withdrawal of a compression sleeve from the loadedprosthesis results in the partial expansion and deployment of lowerflange 24. In FIG. 10C, the compression sleeve has been withdrawn evenfurther, such that a greater portion of lower flange 24 has expanded.FIG. 10D depicts the implantation process at the point when thecompression sleeve has been fully withdrawn, lower flange 24 is bentback towards middle region 28, which is fully expanded and exertingradial force against the mitral valve annulus. Loose tissue on theventricular side of the mitral valve annulus has been grasped by lowerflange 24, and clamped between lower flange 24 and stent middle region28. Upper flange 22 is also in the fully expanded state, has graspedloose tissue on the atrial side of the mitral valve annulus, andfunctions as a “cap” over the tissue on the atrial side of the annulus.

Example 1—Percutaneous Implantation Via Transfemoral Approach

An exemplary delivery and implantation procedure may be performed asfollows using the presently disclosed system for delivering a valveprosthesis, as well as a valve prosthesis according to the presentdisclosure.

First, the femoral vein (right or left) is accessed and a vascularsheath is inserted using the seldinger technique. The atrial septum iscrossed via standard transseptal technique, and an atrial hole iscreated/enlarged via balloon dilation septostomy (10-15 mm angioplastyballoon)

A super-stiff guidewire is carefully shaped to and then positioned inthe left ventricle through the newly created atrial hole. The femoralvenous access site is made larger or “dilated up” with sequentiallylarger vascular dilators sized appropriately to match the diameter ofthe delivery system.

The valve prosthesis is compressed and positioned on the dock of thedelivery system, and the system is otherwise prepared for insertion intothe femoral vein. The loaded delivery catheter is advanced over thewire, into the femoral vein, through the venous system, across theatrial septal defect and then positioned at the level of the mitralannulus using ECHO (transesophageal and or Intracardiac) andfluoroscopic guidance. The steering mechanism is used to navigate theleading tip of the catheter through the vasculature and across theseptum.

Once in position across the mitral annulus, deployment of the prosthesisis accomplished by sequentially withdrawing the containment sleeves,allowing the stent to expand. If necessary, the stent can be forcefullyexpanded to its nominal configuration by inflating a balloon located inthe dock portion of the delivery catheter.

ECHO and fluoroscopic assessment is used to confirm position andstability of the device. If all looks stable, the delivery catheter iswithdrawn from the body. A large vascular sheath is placed into thefemoral vein to promote hemostasis. The atrial septal defect is closedusing a percutaneous closure device (Amplatzer or Helex).

Example 2—Calculation of “Extraction Force”

In situ, the prostheses according to the present invention exert anumber of different forces on the valve annulus and surroundingmaterial. Such forces contribute to the unique ability of the prosthesisto remain anchored and properly positioned at the site of implantation.For example, the upper and lower flanges respectively bend back towardsthe middle region of the stent, and any tissue that is interposedbetween a flange and the middle region will be grasped by the flange andclamped between the flange and the middle region. The stent also exertsan outward radial force against the walls of the valve annulus. Althoughsuch forces can be difficult to measure individually, the force that isrequired to extract an implanted prosthesis represents one proxy of theaggregate the various forces that are exerted by the stent.

An experiment was conducted to measure the extraction force of anexemplary prosthesis. The test was conducted using a freshly excisedsheep heart that was externally fixed in a custom-designed box that wasbuilt to hold the heart in a stable, upright position. First, a leftatriotomy was performed to expose the mitral annulus. The prosthesis wasthen deployed into the mitral annulus under direct visualization.Sutures were looped through the atrial arms of the device, gathered intoa central confluence and then knotted together being careful to keepeach suture strand an equal length (much like the chords of a parachutecome to a confluence at the back of the parachutist). Using a forcegauge, the knotted sutures were pulled backward, using graduallyincreasing force to dislodge the device from the mitral annulus. Thetarget for this process was that at least 15 Newtons of force would berequired to extract the prosthesis. In fact, the prosthesis remainedaffixed to the annulus at 15 Newtons, and could not be extracted untilthe mitral valve and chordal tissue began to tear, at a point whengreater than 20 Newtons was measured. Accordingly, the aggregate of theforces that were exerted by the prosthesis on the site of implantationenabled the device to adhere to the annulus even when significantextraction forces were applied.

Those skilled in the art also will readily appreciate that manyadditional modifications are possible in the exemplary embodimentwithout materially departing from the novel teachings and advantages ofthe invention. Accordingly, any such modifications are intended to beincluded within the scope of this invention as defined by the followingexemplary claims.

What is claimed:
 1. A prosthetic device comprising: an at leastpartially self-expanding stent adapted for percutaneous delivery andanchoring in a mitral valve annulus, said stent comprising an expandedand an unexpanded state; a long axis; a middle region having first andsecond ends and comprising a framework that defines inner and outersurfaces; a lower flange portion at the first end of the middle regionthat comprises a plurality of flange elements, each of said elementshaving a first end that is attached to the middle region and an opposedsecond end that is spaced from the first end; an upper flange portion atthe second end of the middle region that comprises a plurality of flangeelements, each of said elements having a first end that is attached tothe middle region and an opposed second end that is spaced from thefirst end; wherein, when said stent is in the unexpanded state, theupper and lower flange portions are oriented substantially along thelong axis of the stent; when said stent transitions from the unexpandedstate to the expanded state, the lower flange portion transitions inspace so that it is no longer oriented substantially along the long axisof the stent; the lower flange portion is adapted to anchor the stentwithin the mitral annulus by grasping tissue at the ventricular side ofthe annulus by enfolding it between the lower flange portion and theouter surface of the middle region as the stent transitions from theunexpanded state to the expanded state; and, the upper flange portion isadapted to anchor the stent within the mitral annulus by grasping tissuebetween the upper flange portion and the outer surface of the middleregion and, a cuff comprising an absorbent material disposed at leastpartially circumferentially around an outer surface of said at leastpartially self-expanding stent, wherein said absorbent material expandsby absorption of a fluid to substantially seal said at least partiallyself-expanding stent at an implantation site, and wherein said expansionof said absorbent material is delayed for a time sufficient to permitpositioning of said at least partially self-expanding stent at saidimplantation site; and a valve comprising at least one leaflet fixedlyattached to an interior surface of the stent.
 2. The prosthetic deviceaccording to claim 1, wherein the absorbent material is implemented as abi-layer system in which an outer layer is a fluid impermeable materialthat prevents the absorbent material from expanding while the at leastpartially self-expanding stent is being placed, said outer layer adaptedto elute off to allow the underlying absorbent material to expand topermit positioning of said at least partially self-expanding stent. 3.The prosthetic device according to claim 2, wherein the absorbentmaterial is a crosslinked hydrogel comprising poly(acrylic acid) and apoly(ethylene glycol).
 4. The prosthetic device according to 2, whereinthe fluid impermeable material comprises a fluid impermeable polymerbarrier deposited on the absorbent material.
 5. A prosthetic devicecomprising: an at least partially self-expanding stent adapted forpercutaneous delivery and anchoring in a mitral valve annulus, saidstent comprising an expanded and an unexpanded state; a middle regionhaving first and second ends and comprising a framework that definesinner and outer surfaces; a lower flange portion at the first end of themiddle region that comprises a plurality of flange elements, each ofsaid elements having a first end that is attached to the middle regionand an opposed second end that is spaced from the first end; an upperflange portion at the second end of the middle region that comprises aplurality of flange elements, each of said elements having a first endthat is attached to the middle region and an opposed second end that isspaced from the first end; wherein, when said stent is in the unexpandedstate, the upper and lower flange portions are oriented substantiallyalong the long axis of the stent; when said stent transitions from theunexpanded state to the expanded state, the lower flange portiontransitions in space so that it is no longer oriented substantiallyalong the long axis of the stent; the lower flange portion is adapted toanchor the stent within the mitral annulus by grasping tissue at theventricular side of the annulus by enfolding it between the lower flangeportion and the outer surface of the middle region as the stenttransitions from the unexpanded state to the expanded state; and, theupper flange portion is adapted to anchor the stent within the mitralannulus by grasping tissue between the upper flange portion and theouter surface of the middle region and a cuff comprising an absorbentmaterial that is a crosslinked hydrogel comprising poly(acrylic acid)and a poly(ethylene glycol) that is disposed at least partiallycircumferentially around an outer surface of said at least partiallyself-expanding stent, wherein said absorbent material expands byabsorption of a fluid to substantially seal said at least partiallyself-expanding stent at an implantation site, and wherein said expansionof said absorbent material is delayed for a time sufficient to permitpositioning of said at least partially self-expanding stent at saidimplantation site; and, a valve comprising at least one leaflet fixedlyattached to an interior surface of the stent.
 6. The prosthetic deviceaccording to claim 5, wherein the absorbent material is implemented as abi-layer system in which an outer layer is a fluid impermeable materialthat prevents the absorbent material from expanding while the at leastpartially self-expanding stent is being placed, said outer layer adaptedto elute off to allow the underlying absorbent material to expand topermit positioning of said at least partially self-expanding stent. 7.The prosthetic device according to claim 6, wherein the fluidimpermeable polymer is deposited on the absorbent material.